Robert%20PERRILLO

1
Robert PERRILLO
2
2nd Paris Hepatitis Conference

Why Do I Treat my HBeAg Negative Chronic
Hepatitis B Patients with Pegylated Interferon
Bob Perrillo Baylor University Medical
Center Dallas, TX USA
3

• They say that to have hepatitis B is to have
  it forever
• But perhaps they were just talking about the
  duration of treatment needed for nucleoside
  analogs

4
Proper Patient Selection Remains Key
Pegylated Interferon Nucleoside
Analog
Age lt 60, otherwise healthy Any age adult
Baseline HBV DNA lt 109 copies/mL Baseline HBV DNA gt 1010 copies/mL
Baseline ALT at least 2-3 x ULN Baseline ALT gt 5 x ULN
Genotype A or B preferentially Any genotype
Non-cirrhotic Cirrhosis, w/wo decompensation
Chemotherapy
Perrillo,
Hepatology, 2006
5
Many Factors Go Into a Treatment Decision
Drug cost /cost of care Indirect costs
Tolerability Convenience Need for monitoring
Finite treatment Diminished
infectivity Durability Potential for
long term benefit
Perrillo, Hepatology, 2006
6
Problems Confronting Clinician with
HBeAg-Negative Hepatitis B

• Becoming the most common form of CHB in world
  today
• High rate of relapse to conventional strategies
• Patients tend to be older with severe disease
• .affects tolerability to IFN
• Little known about predictors of sustained
  virologic response to IFN

7
Comparative Experience with Current Drugs in
HBeAg (-) CHB
IFN alfa Lam ADV ECV Peg IFN
Antiviral activity /
Resistance None 25 68 at 1-5 yrs 0 - 28 at 1-5 yrs lt 1 to yr 2 None
EOT Resp. At 12 mo 46-54 65-85 70-75 84 36
SVR 22-30 lt10-15 8 NA 36
On Rx Response at 24 Mos 46 52-65 71-73 NA NA
After Hadziyannis and Papatheodoridis, Semin
Liver Disease, 2006
8
Problems Confronting Clinician with HBeAg
Negative Hepatitis B

• Becoming most common form of CHB in world today
• High rate of relapse to conventional strategies
• Patients tend to be older with severe disease
• Little known about predictors of sustained
  virologic response to IFN

9

• 216 Naïve Patients
• 3 MU tiw x .7-6.9 mos
• or
• 3 MU tiw x 7.2-13 mos
• 51 retreated
• Relapse
• 1.6 x more likely with
• short course
• Sustained remission
• 3.5 times more likely if
• biochemica/virologic
• response by mo 4

10
Factors Associated with Relapse After 12 Months
of Standard IFN (63 Patients)
ALT-0
Hazard Ratio
Univariate Multivariate
prior ETOH gt 60 gm/d
HBV DNA lt 10,000 copies at treatment mo 6
age
gender
alcohol
P 0.089 P 0.032
ALT-0
HBV DNA
grade
stage
Baltayiannis Aliment
Pharmacol Ther, 2006
11
Prolonged PCR Negativity Does not Allay Concerns
About Relapse
Virologic relapse
0.8

• 50 Chinese patients
• treated with LAM
• 37 treated for 2 yrs
• 27 neg. by PCR
• for 9 mos meet
• criteria for treatment
• withdrawal

Clinical relapse
0.6
0.4
0.2
Months to Relapse
0- 2 4 6 8
10 12 14 16 18
Fung, 2004
12
Worldwide Distribution of HBV Genotypes
Asia 1
Europe 1
Mediterranean 1
USA 2
1 Westland, Gastroenterology 2003 2 Chu,
Gastroenterology 2003
13
Response to PEG-IFN a-2a by Genotype
HBsAg-seroconversion in HBeAg neg patients (EOF
in 177 patients)
25
18
20
15
Percentage of patients ()
10
3
2
5
0
0
B n43
C n63
D n55
A n11
Hadziyannis, EASL 2005
14
Predicting Response to Peg IFN 2a, Lam or Both
for HBeAg (-) CHB 24 Week Post Treatment
60
Peg IFN alfa-2a
Lamivudine
Peg IFN Lamivudine
50
36/69
44
31/63
40
19/43
37
19/49
20/54
30
22
16
20
15/57
9/41
2/10
9/55
10
1/8
7/63
3/11
0
Genotype A
Genotype B
Genotype C
Genotype D
Bonino, in press, GUT
ALT normal and HBV DNA lt 20,000 copies
15
Conventional IFN? HBsAg Clearance in
HBeAg-negative CHB

• 4.515 of all IFN? treated patients
• 3645 of sustained responders at 57 years
• Anti-HBs-positive gt 90 of those who clear HBsAg

Manesis EK, et al. Gastroenterology.
2001121101-109. Lampertico P, et al.
Hepatology. 200337756-763.
16
During median fu of 7 yrs, HBsAg loss in
18 of 57 SVRs (32) vs 1 NRs
Cumulative HBsAg Loss In SVRs
Naive
Retreated
Cumulative Rate of HBsAg Loss in SVRs
Yrs From 2 5 7 Start of Rx

Retreated
One IFN Course
11 25 36
5 69
Retreat
17
HBsAg Levels with IFN Alfa and Lamivudine in
HBeAg (-) CHB

• 315 sera from 44 patients analyzed for HBsAg/ HBV
  DNA
• HBsAg quantitated at multiple time points
• No correlation between BSL HBsAg and HBV DNA
• HBsAg decreased in both treatment groups
• - Sharp drop in most IFN treated patients
  continued drop after
• treatment if SVR
• - More gradual slope for LAM EPTU for HBsAg
  is median of 18 yrs of treatment
• 
  Manensis, EASL, 2005

18
Measuring HBsAg in HBeAg (-) CHB with
Extension of Peg IFN Alfa -2a
HBsAg ng/mL Baseline Treatment Week 12 Treatment Week 60 Follow up Week 12 Follow up Week 24
Resp 1 6,515 7,257 19 77 0
Resp 2 gt7692 gt7692 273 446 205
Resp 3 1,619 566 9 20 61
Resp 4 gt7,692 196 38 27 19
NR 1 1,212 1,056 NA 1,910 1,473
NR 2 6,881 gt7,692 6,088 6,823 5,219
NR 3 368 392 304 NA 189
NR 4 5,019 6,030 7,584 6,161 7,715
Response PCR negative at FU week 24
Perrillo, 2006
19

• Why Is HBsAg Clearance So Important?

20
Qualitative Differences Between HBsAg Loss and
HBeAg Seroconversion

• Durability of virologic response
• Lower levels of genomic template (cccDNA)
• Better long-term prognosis
• Less Liver cancer
• Lower rate of progression to cirrhosis
• Less chance of viral reactivation
• Spontaneous
• Immune suppression related

21
PEG IFN alfa-2a in HBeAg (-) CHB Two Years
Post-treatment Follow-up
Initial study
Long-term study
PEGASYS 180 µg placebo (n 116)
PEGASYS 180 µg qw placebo qd
PEGASYS 180 qw lam qd (n 114)
PEGASYS 180 µg qw 100 mg lam qd
Lamivudine 100 mg qd
48 weeks
2 yearspost-EOT
5 years post-EOT
EOT (week 48)
6 monthspost EOT (week 72)
Marcellin et al. NEJM
2004
22
Six Month and 2 Year Post-treatment Responses in
HBeAg (-) CHB
6 MO POST TRT (n 177 ) 2 YR POST TRT (n 116)
ALT Normal 591 322
HBV DNA lt 20,000 copies/mL 431 492
HBV DNA lt 400 copies 191 162
HBsAg loss 41 92

1Marcellin, NEJM, 2004 2Marcellin, AASLD, 2006
23
Other Considerations
24
Cost-effectiveness of IFN?-Based Therapies

• IFN? more cost effective over long-term than
  lamivudine or adefovir in HBeAg-negative CHB1
• PEG-IFN?2a offers life expectancy benefits over
  lamivudine at a favorable cost-effectiveness
  ratio in patients with HBeAg-positive or
  HBeAg-negative CHB2,3

1. Kanwal F, et al. Ann Intern Med.
2005142821-831. 2. Sullivan SD, et al. APASL
2005. Abstract 135. 3. DL Veenstra, et al. APASL
2005. Abstract 132.
25
Peg Interferon Alfa-2b Plus Adefovir Effect on
cccDNA and HBsAg Reduction

• Serum HBV lt 100 copies
• Hepatocyte total HBV DNA reduction
• Hepatocyte cccDNA reduction
• Serum HBsAg reduction
• HBsAg seroconversion

13/24 (54) -2.2 log -2.4 log - 0.6 log 4/24
(17)
Wursthorn, Hepatology, 2006
26
HBeAg Negative Chronic Hepatitis BRationale for
Pegylated IFN First

• Lasting responses to finite therapy avoids long
  term
• treatment with nucleoside analogs
• Predictors of response are becoming better
  identified
• HBsAg concentration decreases during therapy and
  decline in level may be predictive of response
  and length of therapy needed

27
Rationale for Pegylated IFN First (cont)

• HBsAg loss occurs in SVRs and this increases as a
  function of time
• Genotype D patients tend not to respond to
• Peg IFN given alone but this group may
  possibly
• benefit from combination therapy (??)
• Patients can be treated subsequently with
  nucleoside analogs without increased risk for
  drug failure should Peg IFN fail to achieve
  benefit

28
Cest fini